Metabolic aberrations in the form of altered flux through key metabolic pathways are primary hallmarks of many malignant tumors. Among the many adjustments of the metabolic pathways that are found in tumor cells, a key role is played by an enhanced aerobic glycolysis followed by lactic fermentation, which is also known as the Warburg effect (Warburg, O. Science, 123:309 (1956)). Normal cells generally transform glucose into carbon dioxide and water under aerobic conditions, by means of oxidative phosphorylation (OXPHOS). On the contrary, invasive cancer cells mostly produce lactate, even in the presence of sufficient levels of oxygen, even though this glycolytic pathway turns out to be less efficient than OXPHOS in producing ATP units. This apparently counterproductive behavior of cancer cells actually constitutes a survival advantage in rapidly proliferating cells, since it makes them insensitive to transient or permanent hypoxic conditions, it contributes to the production of nucleosides and amino acids, and constitutes a very rapid way to produce energy due to the enhanced glucose uptake occurring in cancer tissues. Lactate is not just a waste product of this process. It promotes tumor invasion by favoring cell migration, angiogenesis, immune escape and radioresistance (Draoui, N, et al., Dis. Model. Mech., 4:727 (2011)). For example, rather than using lactate as a nutrient, cancer cells generally export lactate, leading to acidification of the tumor environment and a local inflammatory response that drives tumorigenesis (Doherty and Cleveland, J Clin Invest. 2013 Sep. 3; 123(9): 3685-3692). Lactate in the tumor cell microenvironment also appears to impair the adaptive immune response, disabling immune surveillance, in part by inhibiting immune cell metabolism.
Targeting this unique tumor metabolism can provide an alternative strategy to selectively destroy the tumor, leaving normal tissue unharmed (Warburg, Science 123:309-314 (1956), Zu et al., Biochem. Biophys. Res. Commun. 313:459-465 (2004), Samudio et al, Cancer Res. 69:2163-2166 (2009), Gatenby et al, Nat. Rev. Cancer 4:891-899 (2004), Kim et al, Cancer Res. 66:8927-8930 (2006), and Cheong et al, Nat. Biotechnol. 30:671-678 (2012)). The orphan drug dichloroacetate (DCA) is a mitochondrial kinase inhibitor that has the ability to show such characteristics. By utilizing the metabolic switch, DCA reverses the abnormal cancer cell metabolism from aerobic glycolysis to glucose oxidation by reducing the activity of mitochondrial pyruvate dehydrogenase kinase 1 (PDK1), which negatively regulates pyruvate dehydrogenase (PDH) causing pyruvate to convert to acetyl-CoA promoting oxidative phosphorylation (Bonnet et al. 2007). DCA reduces the high mitochondrial membrane potential (ΔΨm) of cancer cells and increases mitochondrial reactive oxygen species (ROS) in malignant cells, but not in normal cells (Pathak R K et al., ACS Chem. Biol., 9:1178-1187 (2014)).
However, therapeutically prohibitive high DCA doses are needed for suppression of tumor growth due to the lack of effective mechanisms for DCA entry into tumor cells and its localization inside the target organelle, mitochondria of cells. One recent study revealed a mitochondria-targeted DCA analogue, MITO-DCA, with a much improved cellular and mitochondrial uptake (Pathak R K et al., ACS Chem. Biol., 9:1178-1187 (2014)). MITO-DCA uses a lipophilic triphenylphosphonium (TPP) cation moiety for the targeted delivery and accumulation into the mitochondrial matrix. The study showed that MITO-DCA efficiently reduced glycolytic functions, reduced basal cellular respiration, suppressed the calculated ATP synthesis, and attenuated the spare respiratory capacity in prostate cancer cells in vitro (Pathak R K et al., ACS Chem. Biol., 9:1178-1187 (2014)).
However, targeted anti-cancer drugs such as MITO-DCA still face many challenges in accessing target sites in vivo, such as premature detachment of inhibitors from the targeting molecule, or fast elimination from the body.
Therefore, it is an object of the invention to provide compositions and methods that increase the stability of targeted anti-cancer agents, and minimize their premature breakdown before reaching their targeted site.
It is another object of the invention to provide compositions and methods that improve encapsulation of anti-cancer agents into drug delivery nanoparticles.
It is a further object of the invention to provide compositions and methods that increase the rate of delivery of therapeutics to disease environment in conditions such as cancer, proliferative disorders, neurodegenerative diseases, autoimmune disorders, or inflammatory diseases, for reducing, or alleviating one or more symptoms.